Resistance to drugs has implied that efflux mechanisms are processes common to all prokaryotic and eukaryotic cells. It has been responsible for failures in treatment in the battles against cancer, parasites and bacteria. A recent analysis of the situation in Europe conducted by the ECDC (European Centre for Disease Prevention and Control) concluded that there is an increasing gap forming between the number of infections due to multiple drug resistant (MDR) bacteria and the number of cases treatable with new antibiotics. Resistance to antibiotics is increasing in Gram-positive as well as Gram-negative bacteria, which cause serious infections in humans. In the European Union, certain Gram-negative bacteria are becoming more resistant, which has recently been observed in the case of Escherichia coli. Every year, approximately 25,000 patients die in the EU (175,000 worldwide) from an infection due to MDR bacteria. Infections due to MDR bacteria induce costs of at least 1.5 billion per year. Currently, production of new agents, targets or mechanisms is lacking for Gram-negative bacteria showing MDR. Therefore, a new strategy has to be put in place in Europe and worldwide to address this problem.
Due to the increasing statistics describing the implication of efflux of antibiotics in inherent (natural) resistance and in the emergence of new MDR bacteria, bacterial efflux pumps have been selected as a possible basis for development of a therapeutic strategy that comprises administration of an antibiotic alongside an efflux inhibitor, restoring thereby its efficiency.
Different strategies are employed to hinder efflux mechanisms. The inhibition of activity of efflux pumps by natural or synthetic compounds represents the state of the art in this approach. These compounds are called “Efflux Pump Inhibitors” (EPI's) and they have the ability to restore the sensitivity of certain bacteria to certain antibiotics. Among these compounds is Phenyl-Arginine β-Naphtylamide (PAβN), which represents the single commercially available active of this type. PAβN is therefore of great importance in the functional study of these mechanisms, which makes up for its lack of clinical application due to its toxicity.
The inventors have significantly helped describe efflux mechanisms of Gram-negative bacteria. They have established model systems, including clinical and genetically modified strains and analytical methods that allow the targeting of compounds capable of inhibiting these mechanisms [1 to 4]. They have identified, on commercial or synthesised molecules, key structures capable of blocking these mechanisms [5 to 10].
In patent application n° EP 2,184,061 A1, the inventors disclose the use of geraniol and saturated or unsaturated monoterpene derivatives as bacterial efflux pump inhibitors.